Adjuvant for promoting absorption of therapeutically active substances through the digestive tract

ABSTRACT

The enamine derivatives having following formula ##STR1## promote absorption of therapeutically active substances through the digestive tract into the blood stream and are able to effectively elevate the concentration of such active substances in the blood stream even when said active substances are usually absorbable through the digestive tract only with considerable difficulty.

This invention relates to an adjuvant for promoting absorption of therapeutically active substances through the digestive tract and a pharmaceutical composition comprising a therapeutically active substance and said adjuvant, said composition being beneficial in that the therapeutically active substance contained therein is readily absorbed into the blood stream through the digestive tract even when said active substance is usually absorbable through the digestive tract only with considerable difficulty.

Several compounds have heretofore been proposed as adjuvants for promoting absorption of medicinal substances through the digestive tract, but have been found to be disadvantageous in that some are useful only for oral application while others are not efficient enough to bring about a therapeutically effective blood concentration of the concomitant active substance.

The intensive search undertaken under the above circumstances into adjuvants which would promote absorption or therapeutically active substances through the digestive tract and particularly for those substances which could be successfully employed for rectal administration has resulted in the finding that enamine derivatives of the following general formula (I) have an excellent absorption-promoting action and that a pharmaceutical composition containing such an adjuvant is capable of ensuring a high and sustained blood concentration of the therapeutically active substance concomitantly present, irrespective of the kind of therapeutically active substance or the dosage forms employed, such as suppositories, tablets, capsules or sublingual tablets, etc.

Thus, this invention relates, in one aspect, to an absorption-promoting adjuvant comprising one or more members of enamine derivatives having the general formula: ##STR2## (wherein ##STR3## means the residue of an organic aminocarboxylic acid or organic aminosulfonic acid with a hydrogen atom removed from its amino group; the carboxyl or sulfo group of said residue being optionally in the form of an alkali metal salt or ester; R₁ and R₂ may as taken together form a ring structure; R₃ is hydrogen atom, lower alkyl or lower alkoxy; R₄ is hydrogen atom, lower alkyl or lower alkoxycarbonyl; R₅ is lower alkyl, lower alkoxy which may optionally be substituted by hydroxyl, carboxyl or lower alkoxycarbonyl, or lower alkylamino substituted by hydroxyl, carboxyl or lower alkoxycarbonyl; When R₃ and R₄ are both lower alkyls, the two may as taken together form a carbocyclic group; when R₄ is lower alkyl and R₃ is lower alkoxy, the two groups may as taken together form an oxygen-containing ring.)

In another aspect, this invention relates to a pharmaceutical composition comprising a therapeutically active substance and said adjuvant.

It is therefore an object of this invention to provide an adjuvant which promotes absorption of a therapeutically active substance through the digestive tract, said adjuvant comprising of one or more enamine derivatives (I).

It is another object to provide a pharmaceutical composition comprising a therapeutically active component and said absorption-promoting adjuvant. Other objects of the invention will become apparent from the following description and claims.

FIGS. 1-7 are graphs showing the effectiveness of the present invention.

Some of the enamine derivatives (I) which may be employed in accordance with this invention are novel compounds. Thus, for example, the compounds represented by the following general formula: ##STR4##(wherein ##STR5##has the same meaning as defined hereinbefore; R'₅ is a lower alkoxy orlower alkylamino group substituted by hydroxyl, carboxyl or lower alkoxycarbonyl) are novel compounds.

Referring to ##STR6##in general formula (I) and (I'), said organic aminocarboxylic acid means a carboxylic acid containing a primary or secondary amino group. Such organic aminocarboxylic acids include not only naturally-occurring alpha-amino acids but also such amino carboxylic acids as p-aminobenzoic acid, phenylglycine, etc. The naturally-occurring alpha-amino acids may beacidic, basic or neutral amino acids. Some di- and tripeptides also come under the definition of said organic aminocarboxylic acids. Thus, there may be mentioned aliphatic monoaminomonocarboxylic acids such as glycine, alanine, valine, leucine, isoleucine, etc.; aliphatic hydroxyamino acids such as serine, threonine, etc.; sulfur-containing aliphatic amino acids such as cysteine, cystine, methionine, etc.; aliphatic monoaminodicarboxylic acids such as aspartic acid, glutamic acid, etc. (inclusive of the compounds obtainable by amidating one of the carboxyl groups of such dicarboxylic acids, such as asparagine, glutamine, etc.); aliphatic diaminomonocarboxylic acids such as lysine, arginine, etc.; aromatic amino acids such as phenylalanine, tyrosine, etc.; heterocyclic amino acids such as histidine, tryptophan, proline, oxyproline, etc.; and so on. As examples of said amino carboxylic acids, which are not naturallyoccurring, there may be mentioned β-aminopropionic acid, γ-aminobutyric acid, anthranilic acid, p-aminobenzoic acid, etc. Thecarboxyl group of such organic aminocarboxylic acids may be in the form of an alkali metal salt (e.g. sodium, potassium or other salt) or an ester. The ester may for example be an alkyl ester of 1 to 6 carbon atoms, preferably one containing 1 to 4 carbon atoms (e.g. methyl, ethyl, propyl or other ester.)

The organic aminosulfonic acid means any of aliphatic, aromatic and heterocyclic sulfonic acids corresponding to said aminocarboxylic acids whose carboxyl groups have been replaced by a sulfo group.

Among such organic aminosulfonic groups are taurine and aminobenzenesulfonic acid. The sulfo group may be in the form of an alkalimetal salt or an ester as mentioned in connection with said carboxyl groups.

R₁ and R₂ are such that either one of R₁ and R₂ may forexample be a lower alkyl group or aryl group substituted by carboxyl and/orsulfo, and these groups may be further substituted by amino, mercapto, lower alkylamino, lower alkylthio, heterocyclic group, aryl group, etc. The other of R₁ and R₂ may usually be a hydrogen atom, although it may be lower alkyl, in which case R₁ and R₂ may as taken together form a ring structure.

In the above connection, the lower alkyl group may for example be an acyclic alkyl group of 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, pentyl, hexyl, etc.; and a cycloalkyl group of 5 to 6 carbon atoms, such as cyclopentyl and cyclohexyl. The aryl group may for example be phenyl, α-naphthyl or β-naphthyl.

The lower alkyl group R₃ in general formula (I) may for example be an acylic alkyl group of 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms,such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl, hexyl, etc. or a cycloalkyl group of 5 to 6 carbon atoms, such as cyclopentyl and cyclohexyl. The lower alkoxy which is also designated by R₃ may for example be an acyclic alkoxy group of 1 to 6 carbon atoms,preferably 1 to 4 carbon atoms, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, pentyloxy, hexyloxy, etc. ora cycloalkoxy group of 5 to 6 carbon atoms, such as cyclopentyloxy, and cyclohexyloxy.

The lower alkyl R₄ in general formula (I) may be any of the lower alkyls named with reference to R₃. The lower alkoxy moiety of lower alkoxycarbonyl R₄ may be any of the lower alkoxy groups mentioned with reference to R₃.

The lower alkyl and lower alkoxy groups R₅ in general formula (I) may be the same as those mentioned with reference to R₃.

The above lower alkoxy group may be substituted by one or more members of the group consisting of hydroxyl, carboxyl and lower alkoxycarbonyl, etc. These substituents may be the same or different.

The lower alkoxy moiety of said lower alkoxycarbonyl group as one of the above-mentioned substituent may be the same as that defined and illustrated with reference to R₃. The lower alkyl moiety of lower alkylamino substituted by hydroxyl, carboxyl and/or lower alkoxycarbonyl, as designated by R₅, may be the same as that defined and illustrated with reference to R₃. This lower alkylamino group may be substituted by 2 or more substituents which may be the same or different. The lower alkoxy moity of lower alkoxycarbonyl in said substituent may be the same as that defined and illustrated with reference to R₃.

When both R₃ and R₄ are lower alkyls, the compound (I) may be represented by general formula (II): ##STR7##(wherein ##STR8##and R₅ are as defined hereinbefore; R₆ is lower alkylene)

The lower alklene group R₆ may be an alkylene group of 1 to 4 carbon atoms, such as methylene, propylene, butylene, etc. When, in general formula (I), R₄ is lower alkyl and R₃ is lower alkyloxy, the compound (I) may be represented by the general formula (III): ##STR9##(wherein ##STR10##and R₅ are as defined hereinbefore; R₇ is lower alkylene)

The lower alkylene R₇ may for example be an alkylene group of 1 to 4 carbon atoms, such as ethylene, propylene and butylene.

Referring to general formula (I'), the lower alkoxy or lower alkylamino group R'₅ as substituted by hydroxyl, carboxyl and/or lower alkoxycarbonyl has the same meaning as defined with reference to R₅ in general formula (I).

The enamine derivative (I) according to this invention can be produced by any procedure analogous to the method described in Chemiche Berichte, 98, 789 (1965). Thus, an organic aminocarboxylic acid, an aminosulfonic acid or an alkali metal salt thereof is reacted with an acylacetate or a β-diketone at room temperature or an elevated temperature. This reaction may be written as follows. ##STR11##(In the above formulas, ##STR12##and R₃ to R₅ are as defined hereinbefore; R₈ is a group which is removable on reaction with an amine.)

Thus, the primary or secondary amino group in said organic aminocarboxylic acid or aminosulfonic acid (IV) reacts with the acyl-acetate or β-diketone (V) or a derivative thereof (VI) to yield the desired enamine derivative. As examples of compounds (V) and (VI), there may be mentioned acetylacetone, propionylacetone, butyroylacetone, methyl acetoacetate, ethyl acetoacetate, n-propyl acetoacetate, isopropyl acetoacetate, n-butyl acetoacetate, isobutyl acetoacetate, tert-butyl acetoacetate, n-pentyl acetoacetate, methoxyethyl acetoacetate, ethoxyethyl acetoacetate, isopropoxyethyl acetoacetate, n-propoxyethyl acetoacetate, α-acetylbutyrolactone, cyclopentanone-2-carboxylic acid methyl ester, cyclopentanone-2-carboxylic acid ethyl ester, cyclopentanone-2-carboxylic acid isopropyl ester, cyclopentanone-2-carboxylic acid n-butyl ester, cyclohexanone-2-carboxylicacid methyl ester, cyclohexanone-2-carboxylic acid ethyl ester, cyclohexanone-2-carboxylic acid propyl ester, ethoxymethylene malonic aciddiethyl ester, ethoxymethylene malonic acid dipropyl ester.

This reaction is generally carried out in a solvent. Solvents which will not interfere with the reaction may be employed and, as examples, isopropyl alcohol, ether, chloroform, dioxane, benzene, ethyl acetate and toluene may be mentioned. The reaction temperature may be a mild one, e.g.room temperature to a moderately elevated temperature.

As mentioned hereinbefore, the enamine derivative (I) is employed as an adjuvant for promoting absorption of therapeutically active substances through the digestive tract. The therapeutically active substances employed in accordance with this invention may be any substances or agentswhich display medicinal effects when absorbed through the digestive tract of the recipient and, therefore, may cover such varied therapeutic drugs as drugs affecting the central nurvous system, antimicrobial drugs, gastrointestinal drugs, drugs affecting metabolism, cardiovascular drugs, respiratory drugs, etc. More specifically, there may be mentioned β-lactam antibiotics such as penicillins and cephalosporins, high molecular substances such as peptides, carbohydrates such as inulin, heparin, etc.. The peptides include insulin, urokinase, lysozyme and so on.

The penicillins include ampicillin, cyclacillin, cloxacillin, benzylpenicillin, carbenicillin, piperacillin, mezlocillin, pirdenicillin,ticarcillin and so on.

The cephalosporins include cephalexin cephalothin, cefoxitin, cefazolin, cephaloridine, cephacetrile, cefotiam, ceforanide and so on.

The pharmaceutical composition containing the absorption-promoting adjuvantaccording to this invention may assume any dosage form in which the therapeutically active substance thereof may pass into the circulation through the digestive tract. For example, oral preparations (e.g. capsules, tablets, etc.), rectal preparations (e.g. suppositories) and sublingual preparations are included. Particularly desirable are preparations for rectal administration.

Any of these dosage forms may be prepared by the established pharmaceuticalprocedures.

Taking rectal suppositories as an example, they may be manufactured in the following manner. First, the enamine derivative (I) is added to a suppository base and, then, a therapeutically active substance is added and dispersed. The resulting mixture is then filled and molded in a suppository container. The order of addition need not be limited to that described above but may be reversed. It is also possible to incorporate anantioxidant, preservative, volume-builder, etc. The suppository base just mentioned may be any known material, oleaginous or water-soluble. The oleaginous base includes, among others, such vegetable oils as peanut oil,olive oil, corn oil, fatty acid glyceride [e.g. Witepsol® (Dynamite Novel Chemicals), SB-Base® (Kanegafuchi Chemical Co., Ltd.), O.D.O® (Nisshin Oil K.K.), etc.] and such mineral oils as paraffin andvaseline.

The water-soluble base includes polyethylene glycol, propylene glycol, glycerin, etc.

The term `digestive tract` as used herein means any and all of the hollow organs of the body which digest and absorb and excrete the nutrients takeninto the body, such as oral cavity, esophagous, stomach, small and large intestines, rectum, etc. While therapeutically active substances are generally not well absorbed when rectally administered, the presence of the adjuvant of this invention in rectal doses assists considerably in theabsorption of therapeutically active substances. Therefore, this invention is especially valuable for application to rectal administration.

The level of addition of enamine derivative (I) is normally 0.5 to 85 weight %, preferably 1 to 20 W%, based on the whole preparation. More specifically, when the therapeutically active component is a β-lactamantibiotic, the concentration of enamine derivative (I) may range from 1 to85 W%, preferably 2 to 20 W%, based on the whole preparation. In the case of insulin, the amount of enamine derivative (I) may range from 0.5 to 20 W%, preferably 1 to 15 W%.

In the case of the rectal preparations, the level of addition of therapeutically active substances is usually 0.0004 to 50 w% based on the whole preparation. More specifically, when the therapeutically active component is a β-lactam antibiotic, the concentration of β-lactam antibiotic may range from 2.5 to 50 w%, preferably from 5 to30 w%, based on the whole preparation. In the case of insulin, the concentration of insulin (24 units/mg) may range from 0.001 to 1 w%, preferably from 0.01 to 0.5 w%. In the case of heparin, the concentration of heparin Na (100 units/mg) may range from 0.1 to 50 w%, preferably from 0.5 to 30 w%. In the case of urokinase, the concentration of urokinase (210000 units/mg) may range from 0.0004 to 0.1 w%, preferably from 0.0005 to 0.01 w%.

In the case of the oral preparations, the level of addition of therapeutically active substances is 15-99 w%, preferably 80-98 w%, based on the whole preparation, when the therapeutically active substances are β-lactam antibiotics.

Production Example 1 [Enamine derivative (I)]

The starting material aminocarboxylic acid or aminosulfonic acid sodium salt or methyl ester (0.2 M) (each of the material compounds mentioned in Table 1) was added to 50-100 ml of isopropyl alcohol, followed by additionof the acylacetate or β-diketone (0.25 M) (also listed in Table 1). The mixture was stirred at room temperature or an elevated temperature until it became a clear solution. The insolubles were then filtered off, the solvent distilled off under reduced pressure and the residue washed with petroleum ether or diethyl ether. By the above procedure were obtained the enamine derivatives (I) having molecular formula shown in Table I, Compound Nos. 1 to 4, 6 to 8 and 10 to 17, (Table 1).

Production Example 2 [Enamine derivative (1)]

The starting material aminocarboxylic acid sodium salt or methyl ester (mentioned in Table 1) (0.2 M) was reacted with diethyl ethoxymethylenemalonate (0.3 M) in 200 ml of benzene under boiling, with the byproduct ethyl alcohol being azeotropically removed.

In 3 to 5 hours, there was obtained a pale yellow solution with small amounts of crystals suspended therein. Following the above reaction, the benzene was distilled off and the residue dissolved in methanol and filtered to remove the insolubles. Then, the methanol was distilled off and the residue washed with petroleum ether or diethyl ether. By the aboveprocedure were obtained enamine derivatives (I) having molecular formula shown in Table 1, Compound Nos. 5 and 9 (Table 1).

The elemental analyses, melting points and ultraviolet absorptions (λmax, ethanol) are given in Table 2.

                                      TABLE 1                                      __________________________________________________________________________     Starting materials                                                             Compound                                                                             Aminocarboxylic acid                                                                       Acyl acetate or                                                                             Molecular formula of products                   No.   Aminosulfonic acid                                                                         β-diketone                                                                             C  H  N  O  S Na                                __________________________________________________________________________     1     Glycine (NA)                                                                               Ethyl acetoacetate                                                                          8  12 1  4  0 1                                 2     γ-Aminobutyric acid                                                      (Na)           "         10 16 1  4  0 1                                 3     (D) Phenylglycine (Na)                                                                        "         14 16 1  4  0 1                                 4        "        Acetylacetone                                                                               13 14 1  3  0 1                                 5        "        Ethoxy methylene malonic                                                       acid diethyl ester                                                                          16 18 1  6  0 1                                 Acetylbutyrolactonealpha.                                                            14          14           1  4  0  1                                      7        "        Cyclopentanone-2-                                                              carboxylic acid butyl                                                          ester        18 22 1  4  0 1                                 8     (D) Phenylglycine                                                                          Ethyl acetoacetate                                                 methyl ester             15 19 1  4  0 0                                 9     (D) Phenylglycine                                                                          Ethoxy methylene malonic                                           methyl ester                                                                               acid diethyl ester                                                                          17 21 1  6  0 0                                 10    (DL) Phenylalanine                                                                         Ethyl acetoacetate                                                 (Na)                     15 18 1  4  0 1                                 11    (DL) Phenylalanine                                                                         Acetylacetone                                                                               14 16 1  3  0 1                                       (Na)                                                                     12    (DL) Phenylalanine                                                                         α-Acetylbutyrolactone                                                                 15 16 1  4  0 1                                       (Na)                                                                     13    (L) Proline (Na)                                                                           Ethyl acetoacetate                                                                          11 16 1  4  0 1                                 14    Taurine (Na)                                                                                  "          8 14 1  5  1 1                                 15    Glycylglycine (Na)                                                                            "         10 15 1  5  0 1                                 16    (L) Glutamic acid (Na)                                                                        "         11 15 1  6  0 1                                 17    (L) Lysine (Na)                                                                               "         18 29 1  6  0 1                                 __________________________________________________________________________     (Na): sodium salt                                                         

The chemical names of the obtained enamine derivatives (I) in Table 1 are as follows:

1. N-(1-Methyl-2-ethoxycarbonylvinyl)glycine sodium salt (Compound 1)

2. N-(1-Methyl-2-ethoxycarbonylvinyl)-γ-aminobutyric acid sodium salt(Compound 2)

3. N-(1-Methyl-2-ethoxycarbonylvinyl)-D-phenylglycine sodium salt (Compound3)

4. N-(1-Methyl-2-acetylvinyl)-D-phenylglycine sodium salt (Compound 4)

5. N-[2,2-bis(ethoxycarbonyl)vinyl]-D-phenylglycine sodium salt (Compound 5)

6. N-[1-(Tetrahydro-2-furanone-3-ylidene)ethyl]-D-phenylglycine sodium salt(Compound 6)

7. N-(2-Butoxycarbonyl-1-cyclopenten-1-yl)-D-phenylglycine sodium salt (Compound 7)

8. Methyl-N-(1-methyl-2-ethoxycarbonylvinyl)-D-phenylglycinate (Compound 8)

9. Methyl-N-[2,2-bis(ethoxycarbonyl)vinyl]-D-phenylglycinate (Compound 9)

10. N-(1-Methyl-2-ethoxycarbonylvinyl)-DL-phenylalanine sodium salt (Compound 10)

11. N-(1-Methyl-2-acetylvinyl)-DL-phenylalanine sodium salt (Compound 11)

12. N-[1-(Tetrahydro-2-furanone-3-ylidene)ethyl]-DL-phenylglycine sodium salt (Compound 12) 13. N-(1-Methyl-2-ethoxycarbonylvinyl)-L-proline sodiumsalt (Compound 13)

14. N-(1-Methyl-2-ethoxycarbonylvinyl)taurine sodium salt (Compound 14)

15. N-(1-Methyl-2-ethoxycarbonylvinyl)glycylglycine sodium salt (Compound 15)

16. N-(1-Methyl-2-ethoxycarbonylvinyl)-L-glutamic acid sodium salt (Compound 16)

17. N,N'-Bis(1-methyl-2-ethoxycarbonylvinyl)-L-lysine sodium salt (Compound17)

                  TABLE 2                                                          ______________________________________                                         Com-                                                                           pound Calculated (%)                                                                              Found (%)    mp     λ max                            No.   C      H      N    C    H    N    (°C.)                                                                          (nm)                            ______________________________________                                         1     45.94  5.78   6.70 45.86                                                                               5.81 6.82 168-171                                                                               281.0                           2     50.63  6.80   5.90 50.65                                                                               6.85 5.96 110-115                                                                               282.5                           3     58.95  5.61   4.91 58.76                                                                               5.70 5.02 226-227                                                                               289.0                           4     61.17  5.53   5.49 61.22                                                                               5.58 5.61 124-126                                                                               311.0                           5     55.98  5.28   4.08 56.12                                                                               5.32 4.12 128-129                                                                               283.0                           6     59.36  4.98   4.94 59.28                                                                               5.03 4.99 159-161                                                                               299.5                           7     63.71  6.53   4.13 63.74                                                                               6.62 4.09 106-109                                                                               299.0                           8     64.97  6.91   5.05 64.12                                                                               6.85 5.11  98-101                                                                               284.5                           9     60.89  6.31   4.18 60.88                                                                               6.34 4.23 <-20   282.5                           10    60.20  6.06   4.68 60.25                                                                               6.05 4.65 182-184                                                                               283.5                           11    62.45  5.99   5.20 62.53                                                                               6.03 5.25 173-175                                                                               313.5                           12    60.60  5.42   4.71 60.72                                                                               5.46 4.18 105-108                                                                               305.5                           13    53.01  6.47   5.62 53.12                                                                               6.45 5.68 >250   289.5                           14    37.06  5.44   5.40 37.03                                                                               5.40 5.43 113-115                                                                               285.5                           15    45.98  5.79   10.72                                                                               45.94                                                                                5.69                                                                               10.82                                                                               129-132                                                                               278.0                           16    43.57  5.00   4.62 43.52                                                                               4.98 4.70 239 (dec)                                                                             284.0                           17    57.13  7.72   3.70 57.08                                                                               7.83 4.60  77- 9 285.5                           ______________________________________                                    

Stability in aqueous solution

To examine the stability in water of the enamine derivatives (I) obtained above, some representative compounds were selected and their half-lives [t0.5 (min.)] in pH 7.4 phosphate buffer (μ: 0.15, temp.: 25° C.) were determined by ultraviolet absorption spectrometry. The results are presented in Table 3. In the Table, "stable" means that the enamine structure was retained even after 6 hours.

                  TABLE 3                                                          ______________________________________                                         Compound No.                                                                             t 0.5 (min.)                                                                               Compound No. t 0.5 (min.)                                ______________________________________                                         1          3.7        10           15.7                                        2         18.8        13           3.1                                         3         26.1        14           24.0                                        4         Stable      15           31.8                                        5         Stable      16           16.3                                        6         478         17           22.9                                        7         Stable                                                               ______________________________________                                    

EXAMPLE 1

    ______________________________________                                         (Recipe 1: capsule)                                                            ______________________________________                                         Ampicillin (briefly, AB-PC) sodium                                                                      15 mg/kg                                              Compound 3               10 mg/kg                                              ______________________________________                                    

Capsules each containing the above indicated amounts of components were prepared by the conventional procedure and administrered to 3 rabbits. Immediately thereafter, each animal was given 20 ml of water and the concentration of AB-PC in the blood was measured by the biological assay method. The mean results are shown in FIG. 1. In the figure, white circlesrepresent AB-PC alone and black circles represent the capsule according to this invention. The absorption-promoting effect of compound 3 appeared 2 to 3 hours after dosing, and in terms of the area under the blood-concentration curve (AUC: μg.min/ml), the results for each rabbitwere 1.52, 1.99 and 1.73, all in excess of 1.5 times of AB-PC alone.

The blood concentrations were measured in conformity with the Antibiotic Standard of Japan. The cup method was employed with Sarcina lutea.

EXAMPLE 2

    ______________________________________                                         (Recipe 2: solution)                                                           ______________________________________                                         Compound 3         250 mg                                                      Water               20 ml                                                      ______________________________________                                    

An oral solution of the above composition was prepared according to the established pharmaceutical practice.

Capsules each containing 15 mg/kg of AB-PC sodium were orally administered to rabbits and immediately thereafter, the above solution was administeredalso by the oral route. The blood concentration of AB-PC (black circles) isshown in FIG. 2. The white circles represent AB-PC alone.

The blood concentrations were measured in conformity with the biological assay method in the Antibiotic Standard of Japan.

EXAMPLE 3

    ______________________________________                                         (Recipe 3: rectal ointment)                                                    ______________________________________                                         CET-Na              20%                                                        Compound 3          10%                                                        Liquid paraffin     35%                                                        White vaseline      35%                                                        ______________________________________                                    

Cephalothin sodium (briefly CET-Na), a drug which is sparingly absorbed from the rectum, was selected for a test. Thus, CET-Na was dispersed in liquid paraffin-white vaseline base to prepare rectal ointment. The ointment was administered to rabbits by the rectal route. FIG. 3 shows thechange in blood concentration (dose: 50 mg CET-Na/kg). A high CET level in the blood could by very quickly achieved. The blood concentration was measured in conformity with the biological assay method in the Antibiotic Standard of Japan.

EXAMPLE 4

AB-PC and cephalexin (briefly, CEX), both of which are sparingly absorbed from the rectum, are also tested. Thus, enamine derivatives (I) and these antibiotics were used to prepare rectal ointments in accordance with established practice. The ointments were administered to rabbits to investigate the peak blood concentrations (μg/ml) and AUC (μg.min./ml). The results are shown in Tables 4, 5 and 6.

    ______________________________________                                         (Recipes 4 to 7: rectal ointments)                                             ______________________________________                                                   AB-PC . Na      10%                                                            Enamine derivative (I)                                                                         10%                                                            Liquid paraffin 40%                                                            White vaseline  40%                                                  Dose:     15mg AB-PC . Na/kg                                                   ______________________________________                                    

Compounds 3, 5, 13 and 14 were used as said enamine derivatives (I) in Recipes 4, 5, 6 and 7, respectively.

                  TABLE 4                                                          ______________________________________                                                              Peak blood                                                Recipe  Enamine      concentration                                             No.     derivative (I)                                                                              (μg/ml)    AUC                                         ______________________________________                                         4       Compound 3   4.8           270                                         5       Compound 5   4.7           149                                         6       Compound 13  2.6           108                                         7       Compound 14  5.9           239                                         ______________________________________                                    

    ______________________________________                                         (Recipes 8 and 9: rectal ointments)                                            ______________________________________                                                   CEX . H.sub.2 O 20%                                                            Enamine derivative (I)                                                                         10%                                                            Liquid paraffin 35%                                                            White vaseline  35%                                                  Dose:     50 mg CEX . H.sub.2 O/kg                                             ______________________________________                                    

                  TABLE 5                                                          ______________________________________                                                               Peak blood                                               Recipe   Enamine      concentration                                            No.      derivative (I)                                                                              (μg/ml)  AUC                                          ______________________________________                                         8        Compound 2   6.7         278                                          9        Compound 13  6.5         733                                          ______________________________________                                    

    ______________________________________                                         (Recipes 10-17: rectal ointments)                                              ______________________________________                                                   CET . Na        20%                                                            Enamine derivative (I)                                                                         10%                                                            Liquid paraffin 35%                                                            White vaseline  35%                                                  Dose:     50mg CET . Na/kg                                                     ______________________________________                                    

                  TABLE 6                                                          ______________________________________                                                               Peak blood                                               Recipe   Enamine      concentration                                            No.      derivative (I)                                                                              (μg/ml)  AUC                                          ______________________________________                                          9       Compound 2   6.3         315                                          10       Compound 3   14.4        445                                          11       Compound 4   11.0        568                                          12       Compound 5   6.1         306                                          13       Compound 8   3.8          49                                          14       Compound 13  2.5          25                                          15       Compound 14  7.8         250                                          16       Compound 15  1.8         102                                          17       Compound 17  8.7         396                                          ______________________________________                                    

EXAMPLE 5

The absorption-promoting effect of the enamine derivative (I) on β-lactam antibiotics has been confirmed in the above experiments. Then, to examine similar effects on drugs having higher molecular weights,insulin which has a molecular weight of 6000 was selected.

    ______________________________________                                         (Recipe 18: rectal suppository)                                                Amorphous insulin      3 I.U.                                                  Compound 3             0.05g                                                   Witepsol H-15®     0.45g                                                   (Recipe 19: rectal suppository)                                                Amorphous insulin      1 I.U.                                                  Compound 3             0.05g                                                   Witepsol H-15®     0.45g                                                   ______________________________________                                    

The blood glucose concentration observed after rectal administration of theabove suppository to rabbits (body weights: 2.0-2.5 kg) is presented in FIG. 4.

The test was conducted by the glucoseoxidase method. The broken line represents the control glucose level (insulin alone added to base). In this case, there has been no absorption of insulin. The white triangles represent the glucose level observed after administration of one I.U. of insulin per animal, while black triangles represent the level after administration of 3 I.U. of insulin per animal. Especially in the latter case, the blood glucose concentration is reduced about 50% from the pre-medication level. The largest depression of blood glucose from the pre-medication level was expressed in % response. The results are shown inFIG. 5. The dose response curve when insulin alone was intramuscularly administered is shown in FIG. 6. The absorption-promoting effect of the adjuvant of this invention was almost comparable to the effect of intramuscular injection.

EXAMPLE 6

    ______________________________________                                         (Recipe 20 - rectal suppository)                                               To investigate the versatility of the absorption-                              promoting action of the adjuvant according to this invention,                  inulin (mol. wt. 5000) was selected as a test polysaccharide.                  ______________________________________                                         Inulin                 0.25g                                                   Compound 3             0.05g                                                   Witepsol H-15®     0.425g                                                  ______________________________________                                    

The above components were used to prepare a suppository in accordance with established pharmaceutical practice. The suppository was rectally administered to rabbits (body weights 2.0-2.5 kg) and the blood concentrations were determined.

The results, shown in FIG. 7, indicates the versatility of enamine derivative (I). The amount of inulin excreted in the urine was 18% of the dose administered.

The following dosage forms (dispersed in Witepsol H-15®) were rectally administered to dogs and humans to measure the urinary recovery rates of inulin. The results were comparable to those obtained in rabbits (Table 7). The test was carried out by the Lunt method.

                  TABLE 7                                                          ______________________________________                                                            Level of addition of                                               Dose of     Enamine derivative                                                                             % Urinary                                   Subject                                                                               inulin      (I)             recovery                                    ______________________________________                                         Rabbit mg/body     Compound 3 10%     8%                                       Dog    "           "          5%     20%                                       Human  "           "          1%     11%                                       Human  "           Compound 1 2%     12%                                       ______________________________________                                    

Production Example 3 [Enamine derivative (I)]

The material amino acids or sodium salts thereof indicated in Table 8 were dissolved or suspended in the solvents also indicated in the same table. The resultant solutions or suspensions were each stirred at room temperature or an elevated temperature. Then, an equimolar amount of ethylacetoacetate was added dropwise and the mixture was stirred for 2 to 10 hours. The solvent was distilled off under reduced pressure and the solid residue was washed or recrystallized. By the above procedure were obtainedthe contemplated products. The physical properties of these products are shown in Tables 9, 10 and 11.

                  TABLE 8                                                          ______________________________________                                         Material amino acid or               Yield                                     sodium salt thereof                                                                            Solvent   Temperature                                                                               (%)                                       ______________________________________                                         18  DL-Alanine (Na) methanol  room     64.5                                    19  L-Alanine (Na)  "         "        60.0                                    20  L-Isoleucine (Na)                                                                              "         "        75.0                                    21  L-Leucine (Na)  "         "        60.0                                    22  L-Threonine (Na)                                                                               "         "        70.0                                    23  L-Methionine (Na)                                                                              "         "        72.0                                    24  DL-Phenylglycine (Na)                                                                          "         "        88.0                                    25  L-Phenylalanine (Na)                                                                           "         "        97.0                                    26  L-Valine (Na)   "         60-80° C.                                                                        98.4                                    27  L-Tryptophan (Na)                                                                              "         "        96.8                                    28  L-Histidine (Na)                                                                               ethanol   room     97.8                                    29  L-Arginine      "         60-80° C.                                                                        80.5                                    30  11-Aminoundecanoic                                                                             "         "        84.3                                        acid (Na)                                                                  31  L-Serine (Na)   "         room     80.5                                    ______________________________________                                         (Na): Sodium salt                                                         

The following contemplated compounds were obtained.

18. N-(1-Methyl-2-ethoxycarbonylvinyl)-DL-alanine sodium salt (Compound 18)

19. N-(1-Methyl-2-ethoxycarbonylvinyl)-L-alanine sodium salt (Compound 19)

20. N-(1-Methyl-2-ethoxycarbonylvinyl)-L-isoleucine sodium salt (Compound 20)

21. N-(1-Methyl-2-ethoxycarbonylvinyl)-L-leucine sodium salt (Compound 21)

22. N-(1-Methyl-2-ethoxycarbonylvinyl)-L-threonine sodium salt (Compound 22)

23. N-(1-Methyl-2-ethoxycarbonylvinyl)-L-methionine sodium salt (Compound 23)

24. N-(1-Methyl-2-ethoxycarbonylvinyl)-DL-phenylglycine sodium salt (Compound 24)

25. N-(1-Methyl-2-ethoxycarbonylvinyl)-L-phenylalanine sodium salt (Compound 25)

26. N-(1-Methyl-2-ethoxycarbonylvinyl)-L-valine sodium salt (Compound 26)

27. α-N-(1-Methyl-2-ethoxycarbonylvinyl)-L-tryptophan sodium salt (Compound 27)

28. α-N-(1-Methyl-2-ethoxycarbonylvinyl)-L-histidine sodium salt (Compound 28)

29. α-N-(1-Methyl-2-ethoxycarbonylvinyl)-L-arginine (Compound 29)

30. N-(1-Methyl-2-ethoxycarbonylvinyl)-11-aminoundecanoic acid sodium salt (Compound 30)

31. N-(1-Methyl-2-ethoxycarbonylvinyl)-L-serine sodium salt (Compound 31)

                  TABLE 9                                                          ______________________________________                                         Compound                  Specific rotation                                    No.         mp. (°C.)                                                                             values [α].sub.D                               ______________________________________                                         18           71-75 (dec)    0 (H.sub.2 O 23°)                           19          157-159 (dec) +187.0 (H.sub.2 O 23°)                        20          166-167 (dec) +152.0 (H.sub.2 O 26°)                        21          147-149       +115.0 (H.sub.2 O 23°)                        22          183-187 (dec) +142.0 (H.sub.2 O 23°)                        23          108-110        +9.0 (H.sub.2 O 23°)                         24          199-201 (dec)  0 (H.sub.2 O 23°)                            25           96.0-97.5    -262.5 (Absolute                                                               alcohol 23°)                                  26           60.0-65.0    +125.0 (Methanol 29°)                         27          118-120 (dec) -260.0 (Methanol 29°)                         28          110-112 (dec) -135.0 (Absolute                                                               alcohol 24°)                                  29          120           +52.0 (Methanol 29°)                          30          180-190 (dec)   --                                                 31          193-194 (dec) +110.0 (H.sub.2 O 24°)                        ______________________________________                                    

                  TABLE 10                                                         ______________________________________                                         Compound                                                                       No.         UV.sub.(mμ).sup.(λ max, ethanol)                                                     IR.sub.(cm.spsb.-1.sub.).sup.(Nujol)               ______________________________________                                         18          287             1630, 1570                                         19          387             1630, 1570                                         20          290             1640, 1620, 1580                                   21          288             1640, 1560                                         22          288             1650, 1610, 1570                                   23          288             1630, 1590                                         24          286             1640, 1560                                         25          288             1630, 1610, 1580                                   26          288             1640, 1590                                         27          284, 290        1630, 1580                                         28          287             1640, 1590                                         29          286             1630, 1570                                         30          284             1640, 1560                                         31          287             1660, 1650, 1620,                                                              1570                                               ______________________________________                                    

                  TABLE 11                                                         ______________________________________                                         Compound                                                                       No.     H.sub.A       H.sub.B     H.sub.C                                      ______________________________________                                         18      9.00   (d,9,1.sup.H)                                                                             1.85  (s,3.sup.H)                                                                          4.20 (a,1.sup.H)                         19      8.96   (d,8,1.sup.H)                                                                             1.85  (s,3.sup.H)                                                                          4.20 (s,1.sup.H)                         20      8.90   (d,9,1.sup.H)                                                                             1.80  (s,3.sup.H)                                                                          4.20 (s,1.sup.H)                         21      8.70   (d,9,1.sup.H)                                                                             1.80  (s,3.sup.H)                                                                          4.15 (s,1.sup.H)                         22      8.87   (d,8,1.sup.H)                                                                             1.86  (s,3.sup.H)                                                                          4.22 (s,1.sup.H)                         23      8.85   (d,8,1.sup.H)                                                                             1.85  (s,3.sup.H)                                                                          4.20 (s,1.sup.H)                         24      9.50   (d,6,1.sup.H)                                                                             1.60  (s,3.sup.H)                                                                          4.22 (s,1.sup.H)                         25      8.85   (d,9,1.sup.H)                                                                             1.46  (s,3.sup.H)                                                                          4.10 (s,1.sup.H)                         26      8.95   (d,9,1.sup.H)                                                                             1.85  (s,3.sup.H)                                                                          4.25 (s,1.sup.H)                         27      8.95   (d,9,1.sup.H)                                                                             1.45  (s,3.sup.H)                                                                          4.05 (s,1.sup.H)                         28      8.85   (d,9,1.sup.H)                                                                             1.60  (s,3.sup.H)                                                                          4.12 (s,1.sup.H)                         29      8.85   (d,9,1.sup.H)                                                                             1.85  (s,3.sup.H)                                                                          4.25 (s,1.sup.H)                         30      --     (disappear)                                                                               1.75  (s,3.sup.H)                                                                          4.35 (s,1.sup.H)                         31      9.00   (d,7,1.sup.H)                                                                             1.80  (s,3.sup. H)                                                                         4.25 (s,1.sup.H)                                                                    (ppm)                               ______________________________________                                         (Note)                                                                         1. The solvent was DMSOd.sub.6, except that D.sub.2 O was used for Compoun     30.                                                                             ##STR13##                                                                

EXAMPLE 7

    ______________________________________                                         (Recipes 21-34: rectal suppositories)                                          ______________________________________                                         Amorphous insulin   6 I.U.                                                     Enamine derivative (I)                                                                             As indicated in                                                                Table 12                                                   Witepsol H-15®  To make a total of                                                             0.5g                                                       ______________________________________                                    

The above components were used to prepare rectal suppositories in accordance with established pharmaceutical practice. The suppositories were administered to rabbits and dogs by rectal route.

Table 12 shows the glucose responses (%) obtained with the above suppositories. The test was conducted by the glucose oxidase method.

                  TABLE 12                                                         ______________________________________                                                            Time course (min.)                                                                                   Return                                                    Blood                to                                                 Kind   glucose              pre-                                  Level of addition                                                                           of     response             medi-                                 of enamine deriva-                                                                          ani-   (6 I.U.) On-   Lowest                                                                               cation                                tive (I)     mal    (%)      set   level level                                 ______________________________________                                         Compound 18,                                                                              1%    R      45-55  30    45-60 180                                 Compound 19,                                                                              1%    R      45-55  30    45-60 180                                 Compound 20,                                                                              2%    D      25-35  60-90 120   180-240                             Compound 21,                                                                              1%    D      35-45  30    60-90 180                                 Compound 22,                                                                              5%    R      40-50  30    45-75 180                                 Compound 23,                                                                             10%    R      30     30    60-90 180                                 Compound 24,                                                                              1%    R      50-65  15    30-60 180                                 Compound 25,                                                                              1%    R      50-65  30    45-90 180                                 Compound 26,                                                                             10%    R      30     30    60-90 180                                 Compound 27,                                                                             10%    R      30     30    60-90 180                                 Compound 28,                                                                             10%    R      30     30    60-90 180                                 Compound 29,                                                                              5%    R      40-50  15    60-90 210                                 Compound 30,                                                                             10%    R      30     30    60-90 180                                 Compound 31,                                                                             10%    R      30     30    60-90 180                                 ______________________________________                                         (Note)                                                                         R: rabbit                                                                      D: dog                                                                    

Production Example 4 [Enamine derivatives (I)]

The amino acids and starting compounds (V) indicated in Table 13 were reacted under the conditions also indicated in the same table. The reaction was carried out in homogenous solution or suspension for 2 to 10 hours.

The reaction was conducted at room temperature or an elevated temperature, with constant stirring. The solvent was then distilled off and the solid residue was recrystallized to obtain the contemplated enamine derivative.

                                      TABLE 13                                     __________________________________________________________________________                    Material                                                           Material    compound (V)*      Tempera-                                     No.                                                                               amino acid  (R.sub.5 in formula V)                                                                       Solvent                                                                             ture                                         __________________________________________________________________________     32 Glycine (Na)                                                                                ##STR14##    Ethanol                                                                             Room                                         33 DL-Alanine (Na)                                                                             ##STR15##    Ethanol                                                                             Reflux                                       34 L-phenylalanine (Na)                                                                        ##STR16##    Ethanol                                                                             Room                                         35 L-arginine                                                                                  ##STR17##    H.sub.2 O                                                                           Room                                         36 L-phenylalanine (Na)                                                                        ##STR18##    Methanol                                                                            Room                                         37 L-phenylalanine (Na)                                                                        ##STR19##    Ethanol                                                                             Room                                         38 Glycine (Na)                                                                                ##STR20##    Ethanol                                                                             Room                                         __________________________________________________________________________     (Note)                                                                         *R.sub.3 = CH.sub.3, R.sub.4 = H                                               (Na): Sodium salt                                                         

The chemical names of enamine derivatives (I) thus obtained are as follows.

32. N-[1-Methyl-2-(1-ethoxycarbonyl-ethoxycarbonyl)vinyl]glycine sodium salt (Compound 32)

33. N-[1-Methyl-2-(1-ethoxycarbonyl-ethoxycarbonyl)vinyl]-DL-alanine sodiumsalt (Compound 33)

34. N-[1-Methyl-2-(1-ethoxycarbonyl-ethoxycarbonyl)vinyl]-L-phenylalanine sodium salt (Compound 34)

35. α-N-(1-Methyl-2-(1-carboxy-ethoxycarbonyl)vinyl]-L-arginine (Compound 35)

36. N-[1-Methyl-2-(2-hydroxyethylcarbamoyl)vinyl]-L-phenylalanine sodium salt (Compound 36)

37. N-(1-Methyl-2-ethoxycarbonylmethylcarbamoyl-vinyl)-L-phenylalanine sodium salt (Compound 37)

38. N-[1-Methyl-2-(2,3-dihydroxypropoxycarbonyl)vinyl]glycine sodium salt (Compound 389

The melting points, UV spectra, IR spectra and specific rotation values of these product compounds are shown in Table 14.

                  TABLE 14                                                         ______________________________________                                                         UV.sub.(λmax)                                                                             Specific                                     Com-            mμ             rotation                                     pound           (95%      IR      value [α].sub.D                        No.   mp. (°C.)                                                                         ethanol)  (cm.sup.-1)                                                                            (Ethanol 20° C.)                      ______________________________________                                                                   1725                                                 32    --        288       1640    --                                                                     1580                                                                           1730                                                 33    --        288       1640    --                                                                     1580                                                                           1730                                                 34    --        292       1640    --                                                                     1580                                                                           1640                                                 35    --        286.5     1570    +34°                                                            1620                                                 36    129-135   287       1580    -183.7°                                                         1610                                                 37    101-104   288       1580    -218.9°                               ______________________________________                                    

The NMR spectra of Compound 32 through 37 are as follows. ##STR21##

                  TABLE 15                                                         ______________________________________                                         Com-                                                                           pound                                      Sol-                                No.   R'     H.sup.A   H.sup.B                                                                              H.sup.C                                                                              H.sup.D vent                                ______________________________________                                         32    C.sub.2 H.sub.5                                                                       8.72      1.85  4.30  4.82    DMSO                                             (t,J=5,1H)                                                                               (s,3.sup.H)                                                                          (s,1.sup.H)                                                                          (q,J=7,1.sup.H)                             33    C.sub.2 H.sub.5                                                                       8.90      1.87  4.23  4.81    "                                                (d,J=7,1H)                                                                               (s,3.sup.H)                                                                          (s,1.sup.H)                                                                          (q,J=7,1.sup.H)                             34    C.sub.2 H.sub.5                                                                       8.80      1.50  4.15  4.82    "                                                (d,J=8,1H)                                                                               (s,3.sup.H)                                                                          (s,1.sup.H)                                                                          (q,J=7,1.sup.H)                             35    H                1.90        4.82                                                               (s,3.sup.H) (q,J=7,1.sup.H)                                                                        D.sub.2 O                           ______________________________________                                    

    ______________________________________                                          ##STR22##               (Compound 36)                                         H.sub.A       9.15 ppm (d, J= 9 Hz, 1H)                                        H.sub.B       1.40 ppm (s, 3H)                                                 H.sub.C       4.10 ppm (s, 1H)                                                  ##STR23##     7.17 ppm (s, 5H)                                                ______________________________________                                          ##STR24##               (Compound 37)                                         H.sub.A       9.50 ppm (d, J= 9 Hz, 1H)                                        H.sub.B       1.08 ppm (s, 3H)                                                 H.sub.C       4.06 ppm (s, 1H)                                                 H.sub.D       1.23 ppm (t, 3H, 7 Hz)                                           H.sub.E       4.10 ppm (q, 2H, 7 Hz)                                            ##STR25##     7.10 ppm (s, 5H)                                                ______________________________________                                    

EXAMPLE 8

    ______________________________________                                         (Recipe 35-41: rectal suppositories)                                           ______________________________________                                         Amorphous insulin       6 I.U.                                                 Enamine derivative (I)  0.025g                                                 Wetspsol H-15®      0.475g                                                 ______________________________________                                    

The above components were used to prepare rectal suppositories in accordance with established pharmaceutical practice. These suppositories were rectally administered to rabbits (R, 2.5-3kg) and dogs (D, 12-13kg). The glucose responses (%) and time courses (min.) are shown in Table 16.

                  TABLE 16                                                         ______________________________________                                                            Time course (min.)                                                                                   Return                                                    Blood                to                                                 Kind   glucose              pre-                                  Level of addition                                                                           of     response             medi-                                 of enamine deri-                                                                            ani-   (6 I.U.) On-   Lowest                                                                               cation                                vative (I)   mal    (%)      set   level level                                 ______________________________________                                         Compound 32,                                                                             5%     R      45-55  15    45-60 150                                 Compound 32,                                                                             5%     D      30-40  30    30-60 120                                 Compound 33,                                                                             5%     R      45-55  15    45-60 150                                 Compound 34,                                                                             5%     R      45-55  15    45-60 150                                 Compound 35,                                                                             5%     R      20-30  15    30-60 120                                 Compound 36,                                                                             5%     R      20-30  15    30-60 120                                 compound 37,                                                                             5%     R      20-30  30    30-60 120                                 Compound 38,                                                                             5%     R      45-55  15    45-60 150                                 ______________________________________                                         R: Rabbit                                                                      D: Dog                                                                    

EXAMPLE 9

Suppositories were prepared in accordane with established pharmaceutical practice, using the recipes shown in Table 17. These suppositories were rectally administered to dogs and the absorbabilities of the active components were investigated by measuring the blood concentrations. The results are shown in Table 17.

The blood concentrations were measured in conformity with the biological assay method in the Antibiotic Standard of Japan. The cup method was employed with Sarcina lutea for penicillins and Bacillus subtilis for cephalosporins.

                                      TABLE 17                                     __________________________________________________________________________     Recipe                                                                         Enamine           Concentration in blood (μg/ml)                            derivative        Body weight                                                                           15 30 60 120                                          (I)    Antibiotics                                                                          base (Dog) (kg)                                                                            min.                                                                              min.                                                                              min.                                                                              min.                                         __________________________________________________________________________     Compound 1                                                                            AB-PC-Na                                                                             SB-W 13.5   1.23                                                                              0.87                                                                              0.61                                                                              0.32                                         60mg   75mg  1065mg                                                            (50%)                                                                          Compound 10                                                                           CET-Na                                                                               Witepsol                                                                            12.0   15.30                                                                             11.73                                                                             6.75                                                                              2.20                                         150mg  500mg H-15                                                              (10%)        850mg                                                             Compound 20                                                                           CET-Na                                                                               Witepsol                                                                            9.8    9.00                                                                              6.23                                                                              2.91                                                                              1.00                                         150mg  500mg H-15                                                              (10%)        850mg                                                             Compound 22                                                                           CET-Na                                                                               Witepsol                                                                            9.5    0.75                                                                              0.57                                                                              0.31                                                                              --                                           60mg   75mg  H-15                                                              (5%)         1065mg                                                            Compound 27                                                                           AB-PC-Na                                                                             SB-W 11.4   1.6                                                                               1.5                                                                               0.74                                                                              0.40                                         120mg  75mg  1005mg                                                            (10%)                                                                          Compound 23                                                                           AB-PC-Na                                                                             Witepsol                                                                            13.0   0.52                                                                              0.34                                                                              0.18                                                                              0.08                                         60mg   75mg  H-15                                                              (5%)         1065mg                                                            Compound 28                                                                           AB-PC-Na                                                                             SB-W 10.5   0.56                                                                              0.44                                                                              0.14                                                                              --                                           60mg   75mg  1065mg                                                            (5%)                                                                           Compound 29                                                                           AB-PC-Na                                                                             SB-W 11.5   0.50                                                                              0.53                                                                              0.61                                                                              0.41                                         120mg  75mg  1005mg                                                            (10%)                                                                          Compound 16                                                                           AB-PC-Na                                                                             SB-W 13.0   0.69                                                                              0.48                                                                              0.52                                                                              0.29                                         120mg  75mg  1005mg                                                            (10%)                                                                          Compound 31                                                                           AB-PC-Na                                                                             Witepsol                                                                            11.3   0.70                                                                              0.38                                                                              0.24                                                                              0.09                                         60mg   75mg  H-15                                                              (5%)         1065mg                                                            Compound 32                                                                           CET-Na                                                                               SB-W 11.5   1.50                                                                              1.12                                                                              0.73                                                                              0.40                                         60mg   75mg  1065mg                                                            (5%)                                                                           Compound 34                                                                           CET-Na                                                                               Witepsol                                                                            9.5    1.25                                                                              0.83                                                                              0.61                                                                              0.39                                         60mg   75mg  H-15                                                              (5%)         1065mg                                                            Compound 36                                                                           AB-PC-Na                                                                             Witepsol                                                                            12.0   1.45                                                                              1.53                                                                              0.80                                                                              0.40                                         120mg  75mg  H-15                                                              (10%)        1005mg                                                            Compound 37                                                                           CET-Na                                                                               Witepsol                                                                            12.5   1.50                                                                              1.28                                                                              0.87                                                                              0.44                                         120mg  75mg  H-15                                                              (10%)        1005mg                                                            __________________________________________________________________________     Na: Sodium salt                                                            

What is claimed is:
 1. A pharmaceutical composition for absorption through the digestive tract, which comprises a therapeutically effective amount of insulin and an absorption promoting amount of an enamine derivative of the formula ##STR26## wherein ##STR27## is the residue of an organic aminocarboxylic acid or organic aminosulfonic acid having a hydrogen atom removed from the amino group thereof, the carboxyl or sulfo group in said residue being optionally in the form of an alkali metal salt or ester; wherein one of R₁ and R₂ is a carboxy or sulfo substituted alkyl of 1 to 6 carbon atoms, cycloalkyl of 5 to 6 carbon atoms, phenyl or naphthyl group and the other of R₁ and R₂ is hydrogen, lower alkyl or phenyl, R₃ is a hydrogen atom, a lower group or a lower alkoxy group, R₄ is a hydrogen atom, a lower alkyl group or a lower alkoxycarbonyl group, R₅ is a lower alkyl group, a lower alkoxy group which may optionally be substituted by hydroxyl, carboxyl or lower alkoxycarbonyl, or a lower alkylamino group which is substituted by hydroxyl, carboxyl or lower alkoxycarbonyl.
 2. A pharmaceutical composition according to claim 1, wherein ##STR28## in the formula is the residue of an organic aminocarboxylic acid having a hydrogen atom removed from the amino group thereof.
 3. A pharmaceutical composition according to claim 1, wherein R₃ in the general formula is a lower alkyl group.
 4. A pharmaceutical composition according to claim 3, wherein lower alkyl group is methyl.
 5. A pharmaceutical composition according to claim 1, wherein R₄ in the general formula is a hydrogen atom.
 6. A pharmaceutical composition according to claim 1, wherein R₅ in the formula is a group selected from the group consisting of ethoxy, 1-ethoxycarbonylethoxy and 1-glyceryl.
 7. A pharmaceutical composition according to claim 1, wherein the enamine derivative is N-(1-methyl-2-ethoxycarbonylvinyl)glycine sodium salt.
 8. A pharmaceutical composition according to claim 1, wherein the enamine derivative is N-(1-methyl-2-ethoxycarbonylvinyl)-L-leucine sodium salt.
 9. A pharmaceutical composition according to claim 1, wherein the enamine derivative is N-(1-methyl-2-ethoxycarbonylvinyl)-L-phenylglycine sodium salt.
 10. A pharmaceutical composition according to claim 1, wherein the enamine derivative is N-(1-methyl-2-ethoxycarbonylvinyl)-DL-phenylglycine sodium salt.
 11. A pharmaceutical composition according to claim 1, wherein the enamine derivative is N-[1-methyl-2-(2,3-dihydroxypropoxycarbonyl)vinyl]glycine sodium salt.
 12. A pharmaceutical composition according to claim 1, wherein the enamine derivative is N-[1-methyl-2-(1-ethoxycarbonyl-ethoxycarbonyl)vinyl]glycine sodium salt.
 13. A pharmaceutical composition according to claim 1, wherein digestive tract is rectum. 